Substituted alkylphenols as hcn1 antagonists
a technology of substituting alkylphenols and hcn1 antagonists, which is applied in the field of substituting alkylphenols as hcn1 antagonists, can solve the problems of large unmet needs for pain relief, large economic cost, and greatly affecting the quality of life of individuals, and achieve the effect of promoting conta
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Compounds are Effective Antagonists of HCN1 Channels when Applied from the Outside in Two Electrode Voltage Clamp (TEVC)
[0264]FIG. 3 shows BP4C-11:0:1 and BP4L-10:0:1 with respect to the hypothetical anchor-tethered 2,6-DTBP. FIG. 4 shows records from three separate cells expressing HCN1-ΔNvΔCv. Each cell was pre-incubated for 20 minutes in recording solution containing 0.04% DMSO alone or with 10 μM BP4C-11:0:1 or BP4L-10:0:1 as indicated. Current-voltage relationships (IVs) were collected with 3 and 5 second activation steps (5 s sweeps shown in each case here). There was no systematic difference in the V1 / 2 reported by the two protocols showing activation was equilibrated at each voltage in both cases under all drug and vehicle conditions (not shown). Sweeps and tails obtained in response to activation at −65 mV are highlighted in black. Tail current activation curves fit with the Boltzmann function are shown for the three cells shown in FIG. 4 (FIG. 5). Data for BP4C-11:0:1 are ...
example 2.2 , 6
Example 2. 2,6-DTBP is a Potent HCN1-Selective Inverse Agonist
[0270]The effect of propofol and 2,6-DTBP on V1 / 2 of HCN1-4 channels. * indicates responses statistically different from control (FIG. 7). Effect of 2,6-(left) or 2,4-(right) di-butylphenols on V1 / 2 of HCN1 channels. The solid line and indicated parameter values are from a fit of the Hill function to the 2,6-DTBP relation; dashed lines are the 2,6-DTBP fit offset by 2-, 15-, and 23-fold for 2,4-DTBP, 2,6-DSBP, and 2,4-DSBP, respectively. The shift in V1 / 2 was significant at >1 μM for DTBPs and at 20 μM for DSBPs (FIG. 8).
[0271]Rank order of HCN1 antagonism as estimated from EC50 is shown in FIG. 9. Tl+-mediated fluorescent quench rate in large unilamellar vesicles, demonstrating that these compounds have minimal membrane effects (FIG. 10). Structure of three 2,6-alklyphenols and their efficacy as general anesthetics (GA) and positive modulators of GABAA receptor (GABAA-R) function (FIG. 11).
[0272]Thus demonstrating that t...
example 3.2 , 6
Example 3. 2,6-DTBP Selectively Suppresses Mechanical and Thermal Hyperalgesia with Respect to Mechanical and Thermal Nociception
[0273]FIG. 12 shows PW,IPS1 and PW,CONTRA (probability of withdrawal of paw ipsi- or contra-lateral to nerve ligation) and effect of indicated cumulative i.p. dose of 2,6-DTBP as a function of stimulus fiber strength (FIG. 12)). FIG. 13A and FIG. 13B show HPWL (hindpaw withdrawal latency) as a function of cumulative i.p. 2,6-DTBP dose at low (15%) and high (30%) stimulus intensity.
[0274]Notably, DTBPs are ineffective as general anesthetics due to lack of efficacy as agonists of GABA-A receptor function; additional data indicate that alkylphenols impair HCN1 gating via a sterically-defined site wherein a hydrogen-bond network contributes to initial binding energy with little involvement in coupling energy.
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